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Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients

Cerny, T. ; Leyvraz, S. ; von Briel, T. ; Küpfer, A. ; Schaad, R. ; Hsu Schmitz, S.-F ; Honegger, P. ; Sessa, C. ; Brunner, J. ; Boddy, A. V.

In: Annals of Oncology, 1999, vol. 10, no. 9, p. 1087-1094

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    Titre
    • Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients
    Auteur
    • Cerny, T.. Department of Oncology Kantonsspilal, St. Gallen
    • Leyvraz, S.. Fondation cle Centre Plurklisciplinaire d'Oncologie, CHUV Lausanne
    • von Briel, T.. Department of Oncology Kantonsspilal, St. Gallen
    • Küpfer, A.. Institut für Klinische Pharmakologie Berne
    • Schaad, R.. Institui für Medizinische Onkologie, University of Berne Berne
    • Hsu Schmitz, S.-F. SIAK Coordinating Center Berne
    • Honegger, P.. Triemlispital Zurich
    • Sessa, C.. Oncology Institute of Southern Switzerland Ospedale S Giovanni, Bellinnzona, Switzerland
    • Brunner, J.. Institui für Medizinische Onkologie, University of Berne Berne
    • Boddy, A. V.. Cancer Research Unit, University of Newcastle upon Tyne UK
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Annals of Oncology, 1999, vol. 10, no. 9, p. 1087-1094. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303231
    Summary
    Background: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide/mesna ± GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. Patients and methods: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. Results: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosup-pression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). Conclusion: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies